Tumor Immune Microenvironment and Clinicopathological Characteristics of Thoracic NUT Carcinoma

This study aimed to provide a detailed clinicopathological, molecular genetics, and immune landscape analysis of a large cohort of primary thoracic NUT carcinomas to identify diagnostic challenges, uncover potential therapeutic targets, and define the spatial heterogeneity of the tumor immune microenvironment (TIME).

Fifty-three thoracic NUT carcinoma cases were analyzed using integrated immunohistochemistry, fluorescence in situ hybridization, targeted RNA sequencing, and multiplex immunofluorescence.

Histologically, the majority of tumors exhibited pleomorphic presentations. Notably, we observed diverse, atypical morphological patterns, including squamous like, basaloid, neuroendocrine tumor like, and undifferentiated, pseudoglandular structure, and lymphoma-like presentations. Immunophenotypically, tumor cells consistently expressed keratins, p63 or p40 and NUT (100%), with focal expression of Syn and CgA in a subset. RNA sequencing identified NUTM1 fusion partners in 20 cases: BRD3::NUTM1, BRD4::NUTM1, NSD3::NUTM1, and notably, the first reported thoracic NUT carcinoma case with YAP1::NUTM1 fusion, which also exhibited SMARCA4 deficiency. Specifically, 2 cases exhibited pseudoglandular structure with myxoid stroma, 1 case displayed a predominantly lymphoma-like morphology, and 2 basaloid cases contained NSD3::NUTM1 fusions. Follow-up data were available for limited 33 patients (8 survivors and 25 deaths). Male sex was associated with improved survival in univariate analysis, whereas fusion type was not an independent prognostic factor. Furthermore, we characterized the TIME of thoracic NUT carcinoma (6 cases), demonstrating the presence of cytotoxic T cells, macrophages, and both mature and immature tertiary lymphoid structures. This heterogeneity in the TIME may contribute to the variable response to immunotherapy in NUT carcinoma.

Primary thoracic NUT carcinoma exhibits significant pathological and immune microenvironmental heterogeneity, which was first described, as evidenced by the identification of a novel YAP1::NUTM1 fusion and diverse immune cell infiltrates. This heterogeneity warrants further investigation because it may inform prognostic stratification and the development of immune-targeted therapies.